Formulations of guanylate cyclase c agonists and methods of use

Abstract

The invention provides novel formulations of guanylate cyclase-C (“GCC”) agonist peptides and methods for their use in the treatment of gastrointestinal diseases and disorders, including gastrointestinal cancer. The GCC agonist formulations of the invention can be administered either alone or in combination with one or more additional therapeutic agents, preferably an inhibitor of cGMP-dependent phosphodiesterase or a laxative.

1 . A GCC agonist formulation comprising (1) a core, which contains at least one GCC agonist peptide, and (2) one or more targeting materials selected from the group consisting of a pH-dependent polymer, a swellable polymer, and a degradable composition, wherein the GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1-249. 
     
     
         2 . The GCC agonist formulation of  claim 1 , wherein the GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1, 8, 9, 55 or 56. 
     
     
         3 . The GCC agonist formulation of  claim 2 , wherein the GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1 and 9. 
     
     
         4 . The GCC agonist formulation of  claim 1 , wherein the formulation is for an oral route of administration. 
     
     
         5 . The GCC agonist formulation of  claim 1 , wherein the formulation is optimized for delivery of a GCC agonist to the duodenum or jejunum. 
     
     
         6 . The GCC agonist formulation of  claim 5 , wherein the formulation comprises one or more pH dependent polymers which degrade in a pH range of 4.5 to 5.5 or in a pH range of 5.5 to 6.5. 
     
     
         7 . The GCC agonist formulation of  claim 1 , wherein the formulation is optimized for delivery of a GCC agonist to the ileum, terminal ileum, or ascending colon. 
     
     
         8 . The GCC agonist formulation of  claim 7 , wherein the formulation comprises one or more pH dependent polymers which degrade in a pH range of 5.5 to 6.5 or in a pH range of 6.5 to 7.5. 
     
     
         9 . The GCC agonist formulation of  claim 6  or  8 , wherein the pH dependent polymer is selected from the group consisting of a methacrylic acid copolymer, a polyvinyl acetate phthalate, a hydroxypropylmethylcellulose phthalate, a cellulose acetate trimelliate, a cellulose acetate phthalate, or a hydroxypropyl methyl cellulose acetate succinate. 
     
     
         10 . The GCC agonist formulation of  claim 9 , wherein at least one of the pH dependent polymers is a methacrylic acid copolymer. 
     
     
         11 . The GCC agonist formulation of  claim 10 , wherein the methacrylic acid copolymer is selected from among the EUDRAGIT polymers. 
     
     
         12 . The GCC agonist formulation of  claim 11 , wherein the EUDRAGIT polymer is selected from among the group consisting of EUDRAGIT L100, EUDRAGIT L-30D, EUDRAGIT S100, EUDRAGIT FS 30D, and EUDRAGIT L100-55, and combinations thereof. 
     
     
         13 . The GCC agonist formulation of  claim 7 , wherein the formulation comprises one or more pH dependent polymers and a swellable polymer. 
     
     
         14 . The GCC agonist formulation of  claim 13 , wherein the formulation comprises two pH dependent polymers which degrade in a pH range of 6.5 to 7.5 and wherein the swellable polymer forms a layer between the two pH dependent polymers. 
     
     
         15 . The GCC agonist formulation of  claim 13 , wherein the swellable polymer is selected from the group consisting of an acrylic copolymer, polyvinylacetate, and cellulose derivatives. 
     
     
         16 . The GCC agonist formulation of  claim 15 , wherein the swellable polymer is an acrylic copolymer selected from the group consisting of EUDRAGIT RL, EUDRAGIT RS, and EUDRAGIT NE. 
     
     
         17 . The GCC agonist formulation of  claim 13 , further comprising a pore forming agent. 
     
     
         18 . The GCC agonist formulation of  claim 17 , wherein the pore forming agent is selected from the group consisting of saccharose, sodium chloride, potassium chloride, polyvinylpyrrolidone, polyethyleneglycol, water soluble organic acids, sugars and sugar alcohol. 
     
     
         19 . The GCC agonist formulation of  claim 1 , wherein the formulation comprises a degradable composition. 
     
     
         20 . The GCC agonist formulation of  claim 19 , wherein the degradable composition is selected from the group consisting of amylase, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin, and xylan. 
     
     
         21 . The GCC agonist formulation of  claim 20 , further comprising a material selected from the group consisting of cellulose acetate phthalate, hydroxy propyl methyl cellulose acetate succinate, EUDRAGIT L100 and EUDRAGIT L30D-55, wherein the material forms an outer coating over the degradable composition. 
     
     
         22 . The GCC agonist formulation of  claim 19 , wherein the degradable composition is a carrier molecule linked to the GCC agonist by a covalent bond, wherein the covalent bond is stable in the stomach and small intestines but labile in the lower gastrointestinal tract, especially the colon. 
     
     
         23 . The GCC agonist formulation of  claim 22 , wherein the covalent bond is an azo bond or a glycosidic bond. 
     
     
         24 . The GCC agonist formulation of  claim 22 , wherein the carrier molecule is selected from the group consisting of a glucuronide, a cyclodextrin, a dextran ester, or a polar amino acid. 
     
     
         25 . A method for treating or preventing a gastrointestinal disease or disorder in a subject in need thereof, comprising administering to the subject a GCC agonist formulation comprising (1) a core, which contains at least one GCC agonist peptide, and (2) one or more targeting materials selected from the group consisting of a pH-dependent polymer, a swellable polymer, and a degradable composition, wherein the GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1-249. 
     
     
         26 . The method of  claim 25 , wherein the formulation comprises one or more pH dependent polymers which degrade in a pH range of 4.5 to 5.5 or in a pH range of 5.5 to 6.5. 
     
     
         27 . The method of  claim 26 , wherein the gastrointestinal disease or disorder is selected from the group consisting of irritable bowel syndrome, non-ulcer dyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, gastro esophageal reflux disease, chronic idiopathic constipation, gastroparesis, heartburn, gastric cancer, and  H. pylori  infection. 
     
     
         28 . The method of  claim 27 , wherein the gastrointestinal disease or disorder is selected from the group consisting of chronic idiopathic constipation and irritable bowel syndrome. 
     
     
         29 . The method of  claim 25 , wherein the formulation comprises one or more pH dependent polymers which degrade in a pH range of 5.5 to 6.5 or in a pH range of 6.5 to 7.5. 
     
     
         30 . The method of  claim 29 , wherein the gastrointestinal disease or disorder is selected from the group consisting of ileitis (post-operative ileitis), Crohn's disease, ulcerative colitis, terminal ileitis, and colon cancer. 
     
     
         31 . The method of  claim 30 , wherein the gastrointestinal disease or disorder is selected from the group consisting of ulcerative colitis and Crohn's disease. 
     
     
         32 . The method of  claim 26  or  29 , wherein the GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1, 8, 9, 55 or 56. 
     
     
         33 . The method of  claim 32 , wherein the GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1 and 9. 
     
     
         34 . The method of  claim 26  or  29 , further comprising administering to the subject an effective amount of an inhibitor of a cGMP-specific phosphodiesterase. 
     
     
         35 . The method of  claim 34 , wherein the cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of suldinac sulfone, zaprinast, and motapizone, vardenifil, and suldenifil. 
     
     
         36 . The method of  claim 26 , further comprising administering to the subject an effective amount of at least one laxative. 
     
     
         37 . The method of  claim 36 , wherein the at least one laxative is selected from the group consisting of SENNA, MIRALAX, PEG, or calcium polycarbophil. 
     
     
         38 . The method of  claim 26  or  29 , further comprising administering to the subject an effective amount of at least one anti-inflammatory agent. 
     
     
         39 . The method of  claim 26  or  29 , wherein the subject is a human.